Significance

The hypothalamic orexin (hypocretin) system controls survival-related processes such as food intake, arousal, and stress. Here we show that orexins also play an important role in learning about stimuli that predict harm. We demonstrate that blocking orexin activity in the noradrenergic locus coeruelus (LC) reduces, whereas increasing its activity enhances, threat learning in a Pavlovian auditory threat conditioning paradigm. Moreover, we demonstrate a direct functional connection between orexin enhancement of LC activity and amygdala-dependent memory processes. Strong, aversive memories can lead to fear and anxiety disorders that have a negative impact on individuals and their quality of life. The orexin system may represent a unique treatment target for these disorders.

Abstract

Survival in a dangerous environment requires learning about stimuli that predict harm. Although recent work has focused on the amygdala as the locus of aversive memory formation, the hypothalamus has long been implicated in emotional regulation, and the hypothalamic neuropeptide orexin (hypocretin) is involved in anxiety states and arousal. Nevertheless, little is known about the role of orexin in aversive memory formation. Using a combination of behavioral pharmacology, slice physiology, and optogenetic techniques, we show that orexin acts upstream of the amygdala via the noradrenergic locus coeruleus to enable threat (fear) learning, specifically during the aversive event. Our results are consistent with clinical studies linking orexin levels to aversive learning and anxiety in humans and dysregulation of the orexin system may contribute to the etiology of fear and anxiety disorders.

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